Compositions and methods for treating, inhibiting the onset, and slowing the progression of erectile dysfunction including naturally occuring age related erectile dysfunction

ABSTRACT

Compositions for treating erectile dysfunction (“ED”), including age related erectile dysfunction (ARED), comprise in a preferred embodiment ginger and an amino acid. Preferably the amino acid is L-arginine and/or L-citrulline. Additionally, the compositions may comprise cortex magnoliae officinalis (CMO) and/or fructus aurantil immaturus (FAI). The compositions of the present inventions are administered in a pharmaceutically effective amount to treat erectile dysfunction. For patients that have noticeable symptoms of ED or for older males, whether or not symptomatic, preferred compositions comprises ginger, L-arginine and/or L-citrulline, CMO, FAI,  Paullinia cupana,  and  Muira puama.

FIELD OF THE INVENTION

The present inventions relate to compositions and methods for treating, inhibiting the onset, and/or slowing the rate of development of erectile dysfunction (“ED”), and in particular relate to compositions and methods for treating, inhibiting the onset, and slowing age related erectile dysfunction (“ARED”).

BACKGROUND

Impotence or erectile dysfunction (ED) is a problem that most men will face at some time in their life. In fact, by the time a man reaches 50 years of age, he has about a 1 in 2 chance of having some problem with his erection; the problem could be either attaining and/or maintaining his erection long enough to complete the sexual act. As men get older, the chance of getting ED increases such that a 60 year old man has approximately a 60% chance of having ED, a 70 year old man has about a 70% chance, etc. Even men in their 40's have about a 40% chance of having some form of ED, while it has been extrapolated that men in their 30's and 20's have about a 30% and 20% chance, respectively, of having noticed that something has changed with their erectile function.

From an anthropological or evolutionary standpoint, the demand on the reproductive organs inclusive of erectile function decreases after men pass their peak reproductive age which ranges from their late teens into their 20's. The actual age of onset of ED in an individual depends on many factors, such as genetics, health, lifestyle, etc. The major reason ED manifests itself, regardless of the age of onset, is due to an alteration in the corporal cavernosal smooth muscle (CSM), which is located within the cavernosal or corporal bodies of the penis.

The function of the CSM in the erectile process is to receive and trap blood entering the corporal bodies. This is accomplished when the CSM undergoes relaxation that allows it to open up and create spaces or sinusoids into which the entering blood pools. The pooling of this blood in sinusoidal spaces increases the pressure within the corporal bodies and when a certain intracorporeal pressure is reached, the pressure closes off the veins that drain the blood out of the corporal bodies, essentially trapping it within the corporal bodies. Clinically, this is how the CSM tissue is able to attain (by creating spaces for the blood to pool into) and maintain (by closing off the veins) an erection. It is when this CSM begins to degrade in some way or another and becomes incapable of either relaxing sufficiently enough to create these spaces where the blood is normally trapped or it cannot maintain its relaxation long enough so that it fails to compress the veins that provide egress for blood from the corporal bodies that ED begins to be manifested. While some men may not notice signs of ED until later in life, it is inevitable that ED will occur if one lives long enough.

There are multiple biochemical pathways involved in penile erection and dysfunction. Without stimulation, flaccidity can be considered as the baseline state. Flaccidity is due to corpus cavernosum smooth-muscle cells (“CSM”) being contracted and helicine arterioles being sufficiently contracted to limit blood flow to corpus covernosal sinuses; the sympathetic nervous system and tonic adrenergic discharge maintain baseline contraction of smooth muscle cells and arteriole blood supply (e.g., adrenergic, cholinergic, and nonadrenergic-noncholinergic pathways). So, a combination of metabolic pathways are involved in inducing the erectile processes involving smooth muscle relaxation, arterial dilation, and venous occlusion.

As noted above, by age 50 about one half of all men will have noticeable ED. The presence of certain diseases, e.g. diabetes, or certain lifestyles, e.g. smoking, may accelerate in time the genetically predetermined onset of the degradation of the CSM such that men with diabetes tend to get ED at a younger age when compared to non-diabetics. It is believed that the degradation of the CSM is ultimately the result of oxidative stress; this oxidation process within the CSM is accelerated by certain diseases (e.g. diabetes), and lifestyles (e.g. smoking), etc. Oxidation of this tissue ultimately results in a progressive loss of the CSM cells and a corresponding increase in collagen fibers or fibrous tissue. At a certain level of loss of the CSM within the corporal tissue, which some estimate to be between 10 and 20% of the CSM cells, the impact on erectile function becomes noticeable. The first recognition that one's erectile mechanism is worsening is the increase in time that it takes for one to achieve subsequent erections. This time in between subsequent erections is called the refractory period and it is the first indication that the CSM tissue is changing for the worse.

When the CSM cells begin to undergo oxidation and deteriorate either as a result of aging or some other cause, the CSM begin to induce an enzyme called inducible nitric oxide synthase (iNOS) which produces nitric oxide in high quantities within the cells that begins to combat the oxidative stress. This induction of nitric oxide (NO) by iNOS is different from the NO that is found in the nerves of the body including the nerves that innervates the CSM cells. This NO in the nerves is produced by a related enzyme called neuronal nitric oxide synthase (“nNOS”) and in the penis it only releases NO when the patient is sexually stimulated. This NO from nNOS is the major chemical that is involved in the relaxation of the CSM cells and hence is required for the initiation and maintenance of a normal erection. Therefore, while nNOS is normally present in the nerves innervating the penis, iNOS is normally not present in the CSM cells of the penis and is only induced by the CSM cells themselves when the cells experience oxidative stress. However, when iNOS is induced as seen in U.S. Pat. No. 5,594,032, human erectile dysfunction can be ameliorated by treatment with iNOS, inducers of iNOS or iNOS cDNA. Further background on sexual dysfunction, urogenital disease, and ED and related treatments can be found in U.S. Pat. No. 6,133,281, U.S. Pat. No. 6,007,824, U.S. Patent Publication 2005/0085486, and Schwartz, Eric, et al., “Sildenafil Preserves Intracorporeal Smooth Muscle After Radical Retropubic Prostatectomy,” The Journal of Urology, Vol 171, pp. 771-774, February 2004.

With reference to U.S. Patent Publication 2005/0085486, fibrotic disease is linked to reproductive disorders and cardiovascular disease, which are both prevalent in aging males. The ubiquitous and long felt need to treat sexual dysfunction has led to surgical and pharmacological treatment approaches. The ongoing commercial success of prescription medications under the trademarks VIAGRA®, LEVITRA® and CIALIS® for treatment of ED demonstrates the long felt and widespread need for effective treatments for ED, particularly for patients that present with ED symptoms advanced sufficiently that erections of satisfactory duration at the desired time can only be reliably accomplished by taking the prescription drug.

Thus, there remains a ubiquitous and long-felt need to treat ED before it progresses to the point where pharmacological and/or other medical intervention is required in order to have desired sexual performance. Nevertheless, current ED drugs, such as VIAGRA® and CIALIS®, are generally prescribed only after the patient has presented with symptoms of ED. These drugs belong to a class of drugs called Type 5 phosphodiesterase (PDE5) inhibitors. PDE5 is an enzyme that breaks down cGMP once it is formed and PDE5 inhibitors like Viagra, Cialis and Levitra prevent the cGMP from breaking down so the effect of the cGMP on the tissues is enhanced. With regards to erectile function, cGMP is formed within the CSM from a reaction that is initiated by the NO that is released from the cavernosal nerve following sexual stimulation. The NO that begins the erectile response comes from the enzyme nNOS that is located in the nerve endings. The NO goes into the CSM cells and causes a reaction to occur in these CSM cells. NO activates the enzyme soluble guanylyl cyclase (sGC) in the cytoplasm of the CSM and this enzyme in turn converts guanosine triphosphate (GTP) into cyclic guanosine monophosphate (cGMP). An increase in cGMP stimulates protein kinase G to phosphorylate potassium and calcium channels causing a decrease in cytosolic calcium, dilation of the helicine arterioles, and the relaxation of the trebecular smooth muscle where all the CSM cells are located. As noted above, the relaxation of the smooth muscle leads to an increase in the intracavernosal volume, initiating the erectile process. Normally, endogenous PDE5 enzyme degrades cGMP which reverses the relaxation of the smooth muscle cells and leads to loss of erection whereas the ingestion of these PDE5 inhibitors prior to sexual stimulation prevent the degradation of the cGMP that is formed thereby prolonging any CSM relaxation and enhancing any erectile response.

Currently, one suffering from ED needs to see a doctor and get a prescription for an ED treatment in advance in order to be prepared for a satisfying experience. Onset and duration of the effects of PDE5 inhibitors like Viagra, Cialis and Levitra depend on the specificity of the compound. While PDE5 inhibitors are considered the “first line treatment of ED,” there are notable side effects (headache, flushing, dyspepsia, rhinitis, visual disturbances, back pain, etc.) and adverse interactions that can limit or bar their use (e.g., patients taking nitrates with a PDE5i can experience hypotension and syncope. See Dorsey, Philip et al., “Phosphodiesterase type 5 (PDE5) inhibitors for the treatment of erectile dysfunction,” Expert Opinion, Pharmacother. (2010), 11(7): pp 1109-1122). Since most men will at some time in their life get ED mainly as the result of CSM deterioration secondary to the aging process, the present inventor faced the problem of whether or not it is desirable to treat men who are asymptomatic but whose refractory period has begun to increase—a subtle sign that the CSM is beginning to undergo deterioration—in order to slow or prevent the progression of this deterioration and the forthcoming ED. For patients who already have noticeable ED symptoms, it may also be desirable to slow if not stop or reverse the progression of the ED.

Prior research indicated that high doses of ginger combined with the iNOS stimulant lipopolysaccharide (LPS) could increase nitric oxide production. However, this conflicted with other work that indicates that ginger by itself and without LPS stimulated iNOS production in a dose dependent manner and in much lower doses (see American Journal of Chinese Medicine, Vol. 32, No. 5, pp 727-735, 2004). Use of high dosages of ginger are impractical for long term routine administration, so initially the present inventor focused on isolating specific compounds within ginger, such as 6-gingerol, that might be utilized in a formulation for stimulating iNOS. However, use of such specific compounds is more expensive, and ginger by itself was insufficient to provide a reasonable alternative to PDE5 inhibitors to treat and/or prevent ED. Thus, the present inventor was challenged by the problems of finding compositions and methods for treatment and inhibition of ED that are practical for long term routine administration, while avoiding side effects of existing formulations, enable treatment of and prevention of ED in patients that cannot utilize prior art ED treatments, and/or provide new practical and cost effective compositions to prevent as well as treat ED.

SUMMARY OF THE INVENTION

The present inventor discovered that ED can be arrested, inhibited, or even reversed by use of a composition of the present inventions and methods of treatment utilizing same. In vitro experiments have established that when inducible nitric oxide synthase (“iNOS”) is stimulated on a daily basis when the penile musculature is deteriorating (e.g., from oxidative stress), penile muscle loss can be inhibited and in some instances new penile muscle tissue forms to replace lost muscle (Ferrini et al. Biol Reprod 76:915-923,2007). Thus, in an embodiment, iNOS stimulation is utilized to treat and/or prevent ED. The inventor also discovered that, to optimize results, the dosages and ingredients of the compositions of the present inventions should be varied depending on the age of the patient or on the onset of ED symptoms. The compositions of the present inventions are particularly useful in the treatment of ARED. The present inventor has surprisingly discovered that dosages of ginger small enough to be useful and practicable in routine, even daily, administration over an extended period of time can be used in compositions of the present invention for treating and inhibiting ED.

Preferred compositions include ginger, and L-arginine or a compound that induces production of L-arginine in vivo. In an embodiment, a composition for the treatment and prevention of ED comprises ginger and L-citrulline, the latter inducing L-arginine in vivo. Treatment for ED includes repeated administration of the compositions of the present inventions to a patient over a period of time sufficient to obtain the desired result. Preferred compositions of the present inventions may not contain compounds that require a prescription and/or avoid side effects of current “first line” treatments for ED. More details of exemplary embodiments of the present inventions follow.

FURTHER DETAILS OF THE INVENTION

Experiments in vitro demonstrated that ginger, also known as Zingiber officinale roscoe (ZOR), at low dosages in the presence of LPS did not appear to stimulate iNOS production. However, the present inventor made the surprising discovery that at higher dosages of ZOR, e.g. 500 mg/L, in the presence of LPS stimulates iNOS. The present inventor also surprisingly discovered that ginger, without separating its ingredients and without the presence of LPS, can cause sufficient stimulation of iNOS to enable much lower dosages of ginger to be used effectively in compositions of the present inventions to treat and prevent ED. For example, in Table 1 below are presented nitrite production data from in vitro experiments with cells incubated with varying amounts of ginger without LPS.

TABLE 1 EFFECT OF GINGER ON NITRIC OXIDE PRODUCTION Cells incubated with differing concen- trations of ginger in the absence of LPS Ginger concentration Nitrite Production (mg/L) (micromolar) Control  0  0.8 ± 0.1 Fresh Ginger  50 36.1 ± 4.2 Fresh Ginger 500 219.8 ± 7.3  Dried Ginger  50 40.8 ± 2.1 Dried Ginger 500 207.7 ± 28.0

The nutraceutical compositions of the present inventions are administered in a pharmaceutically effective amount to treat erectile dysfunction. Treatments can consist of either short term self administered oral dosages taken periodically, e.g. at least once a day or other period of time in between dosages until the desired effect is reached or as part of one's long term, even life time, daily nutrition.

The present inventor found with in vitro experiments that dosages of ginger low enough to be practicable for routine administration are capable of use to treat ED when used in the compositions and methods of the present inventions. Also, by varying the ratio of ginger to other ingredients, the formulations and dosing schedule can be optimized for specific patients and/or patient profiles. One method to determine patient profiles is by obtaining a biopsy of the penile tissue to evaluate the integrity of the CSM cells. Obtaining biopsy specimens of penile tissue can be performed in a relatively painless manner, either during the performance of other surgical procedures e.g. during prostate surgery or even an office visit at which an analgesic/local anesthetic can be used prior to the biopsy. See Schwartz, Eric, et al., “Sildenafil Preserves Intracorporeal Smooth Muscle After Radical Retropubic Prostatectomy,” The Journal of Urology, Vol 171, pp. 771-774, February 2004. In the alternative, blood or other non-penile tissue may be obtained for DNA analysis. Patients at risk for developing ED can be identified by these various methods. Whether via biopsy or other means e.g. DNA analysis, patients susceptible to ED can be identified and treatment with formulations of the present invention or other treatments can be started prior to ED symptoms becoming sufficient to interfere with normal sexual function. In fact, in some cases it is believed that a decrease in smooth muscle cells may be reversed sufficiently to allow patients to improve their erectile function.

In an embodiment, a composition for the treatment of erectile dysfunction comprises cortex magnoliae officinalis and/or fructus aurantil immaturus (also referred to hereinafter as “CMO” and “FAI” respectively; while not wishing to be limited to a particular theory of pharmacologic action, these compounds stimulate nitric oxide).

Ginger is a complex natural composition having numerous purported properties when used alone and/or combination with other compounds. For example, traditional Chinese medicines have used or included ginger in compositions to treat or prevent various maladies based on a variety of metaphysical reasons. Over the past century, scientific methods have shown that many traditional Chinese medicines do not produce the purported effects and/or may even make the target maladies worse. Nevertheless, some traditional Chinese medicines have been found to contain active agents that may be of medical use, even if not effective or safe for the use purported by traditional Chinese medicine. The complexity of ginger and its myriad properties is reflected, for example by certain constituent compounds which have the following structure:

wherein, for example, in 6-gingerol the R sidechain of the vanillyl function group (i.e., 4-hydroxy-3-methoxyphenyl group) is:

Thus, 6-gingerol (also called gingerol) is (S)-5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)-3-decanone and has the following structure:

Since ginger contains multiple compounds, of varying complexity and chemical activity, there are multiple biochemical pathways involved in erectile function and dysfunction, and there are conflicting teachings in the prior art about the biological activity of compounds that might be useful in inducing NO production or otherwise having a potential role in treatment, there remains considerable unpredictability about how to understand, much less control, the relevant metabolic pathways. In fact, the prior art teaches that compositions that contain ginger, for example Danzhixiaoyao Wan, actually inhibit nitric oxide production, i.e., could cause erectile dysfunction (see Liao, Hui et al., “Elucidation of Danzhixiaoyao Wan and its Constituent Herbs on Antioxidant Activity and Inhibition of Nitric Oxide Production,” eCam, Advanced Access publication Jan. 9, 2007). Nevertheless, the same article indicates that ZOR (ginger) at 500 mg/L “seemed to stimulate nitric oxide production” but had no effect at 50 mg/L. In contrast, the present inventor has surprisingly discovered that ginger at low doses in compositions of the present invention can be effectively used to treat ED.

Preferred amounts of ginger in compositions of the present inventions comprise between about 1 mg and about 2 grams. The compositions further comprise about 10 mg to about 2 grams L-citrulline. About 10 mg to about 2 grams L-arginine can be used in place of and/or in addition to L-citrulline. However, since it has been discovered that a larger amount of in vivo L-arginine for use in endogenous production of NO can be induced by a smaller dosage of L-citrulline than of oral L-arginine, preferred compositions of the present invention include L-citrulline in place of and/or in addition to L-arginine (see Schwedhelm et al., British Journal of Clinical Pharmacology, 65: pp 51-59, (2007)).

Further, the compositions of the present inventions are believed to be surprisingly beneficial for the cardiovascular system, and can also be utilized in the treatment of cardiovascular disease. For example, compositions and methods of the present inventions can be used for treating cardiovascular disease manifesting in hypertension.

A preferred composition for treatment of penile muscle degradation in men that do not exhibit substantial or noticeable symptoms of ED contains about 100 milligrams to about 2 grams ginger and about 500 milligrams to about 3 grams of L-citrulline. An alternative composition comprises about 100 milligrams to about 2 grams ginger and about 500 milligrams to about 3 grams of L-arginine. While the present inventor has found a composition using 210 milligrams of 6-gingerol (85%) to about 1 gram of L-arginine to be effective, as noted above the use of ginger is preferred as it has been found to be effective at surprisingly low dosages in compositions of the present invention. Compositions of the present inventions are also useful in treatment of men of any age whether or not ED symptoms are noticeable. As used herein, treatment includes slowing or inhibition of further deterioration of the penile corporal cavernosal smooth muscle even when symptoms of ED are not noticeable. Repeated dosages of compositions of the present inventions can be provided over extended periods of time until the desired effect is obtained. Repeated administration of the compositions of the present inventions to patients demonstrating ED symptoms can be made until desired ED treatment results are obtained, and may be continued thereafter as a prophylactic. The compositions can also be used as a prophylactic against eventual ED symptom manifestation in patients likely to demonstrate same.

It is believed that the fibrotic processes within the penis that are associated with ED may begin at any age. Administration of the compositions of the present invention to a patient that has not noticed an increase in the refractory period, decrease in duration of erection, and/or insufficient tumescence of erection may also be referred to as preventing ED. However, since almost all men will ultimately develop some form of ED with age, and by age 40 a significant percentage of men experience noticeable symptoms of ED, what may be referred to as prevention is likely a treatment that slows or stops further progression of the causes of ED. Preferably, as part of a daily vitamin or other nutrition routine, a pharmaceutically effective amount of compositions of the present invention are taken regularly, if not daily, by males between the age of 20 and 40 (if not sooner).

For patients that have noticeable symptoms of ED, regardless of age, or for older males, whether or not symptomatic, a preferred nutraceutical composition comprises ginger, L-arginine or L-citrulline, FAI, CMO,. Paullinia cupana, and Muira puama. Since certain preferred compositions of the present inventions comprise compounds found in foods or extracted from foods, they may be referred to as “nutraceuticals.” While nutraceutical compositions have traditionally been found in a medicinal format, such as capsules or tablets, an increasing number of foods have been fortified with nutraceuticals. Analogs and/or homologs of ginger constituents that have activity in promoting iNOS sufficient to ameliorate, stop or reverse fibrotic events associated with ED may also be used in combination with L-arginine and/or L-citrulline. The present inventions can therefore be administered in a wide variety of ways and forms matching the lifestyle and dietary preferences of the users. Further, predicate studies of sildenafil have been performed (i.e., Schwartz et al) to show beneficial impact on smooth muscle cells, making it more practical and/or feasible to conduct such studies.

Significant medical advancements have resulted from the use of natural products in either their native form, as extracts, or concentrates. For example, acetylsalicyclic acid (or Aspirin) was derived from Willow trees. Likewise, the anticancer drug Taxol was isolated from the Western Yew tree. As a result natural products have been used for treating various diseases for many years. Many natural products have been purported to increase sexual potency, treat sexual problems, or act as aphrodisiacs. However, there is a great deal of unpredictability due to the complexity of biological systems, variations in plants and their derivatives based on the soil and climate, as well as interactions with other compounds, etc.

The present inventor found that by addition of certain natural products, the symptoms of ED appear to be reduced beyond the predicted bioavailability of the compositions of the present inventions; this may be due to growth or restoration of penile CSM, although the invention should not be limited to a particular theory of operation. Examples of natural products that the present inventor found that can enhance the effectiveness of and prolong the effects of ED treatment include Muira Puama, which is derived from shrubs and trees found in Brazil, and Paullinia cupana (also known as guarana), which is derived from a climbing shrub that grows wild in the Amazon regions of Brazil and Uruguay. Muira Puama and Paullinia cupana appear to enhance sexual desire. In an embodiment designed for men showing symptoms of ED, regardless of age, preferred compositions for the treatment of ED comprise from about 100 mg to about 2 grams ginger, about 1 g to about 3 g L-arginine or an amount of L-citrulline sufficient to produce the same amount of L-arginine endogenously as about 1 gram to about 3 grams L-arginine and/or that have the same effect on NO production in vivo as L-arginine. Preferably, a composition of the present inventions comprises about 250 mg to 2 grams L-arginine (and/or L-citrulline equivalent), about 500 mg Paullinia cupana, and about 100 mg to about 3 g Muira Puama, preferably about 500 mg to about 1.5 g Muira Puama. The forgoing formulation above may additionally or in place of ginger contain about 20 mg to about 1000 mg 6-gingerol, preferably about 220 mg 6-gingerol, although the present inventor has found it preferable to use ginger. In an embodiment, a preferred composition for the treatment of ED, particularly ARED, comprises about 100 mg to about 3 grams ginger, preferably about 2 grams ginger, about 1 g L-arginine, or an amount of L-citrulline sufficient to produce the same amount of L-arginine endogenously, about 500 mg Paullinia cupana, and about 500 mg to about 1.5 g Muira Puama. The foregoing compositions may also contain CMO and/or FAI, preferably in small amounts from 10 mg to 1 gm and preferably in equal amounts. The formulation above may additionally or in place of ginger contain about 20 mg to about 1000 mg 6-gingerol, preferably about 220 mg 6-gingerol, although the present inventors have found it preferable to use ginger.

A substantial percentage of men at some time in their late twenties and thirties begin to notice that their refractory period begins to increase. This is most likely due to some deterioration beginning to occur in the CSM. Indeed, treatment of men in their 30's who have normal erectile function as measured by the IIEF with the PDE5 inhibitor Viagra increased erectile function as measured by the IIEF and a decrease in the refractory period was possibly due to longer term benefits of the drug, although this could simply be enhanced relaxation of the CSM (Mondiani et al. Int J of Imp Res. 15:225-28, 2003). When men start using these drugs, it is not unusual that after a while, the drugs may begin to lose their effectiveness. When this occurs, it is believed to be due to the continued deterioration of the CSM that occurs with aging rather than tachyphylaxis which is a condition where the tissues lose their reactivity to the drug (Musicki et al. J Urol 174:1493-6, 2004).

Therefore, most men in their late 20's or early 30's who have not had any decrease with their refractory period as well as any man in their 20's and 30's whose refractory period is beginning to increase are those who are candidates to take this composition of the present invention. In addition, any man who is beginning to develop symptoms of ED may also be a candidate for this regimen with the hope that the compositions of the present inventions, taken once daily, will halt or at least slow the progression of the deterioration of the CSM and not further exacerbate preexisting ED treatment and evaluation. In an embodiment, testing for ED is performed with a questionnaire called the IIEF (International index of erectile function or similar terminology). Patients on any treatment regimen for ED may be followed with this IIEF scoring system and this can be performed on an annual basis to monitor progression of the ED. With ginger, some patients may experience heartburn, bloating, and stomach upset but these are rare. Ginger in daily doses much higher than the purported daily doses in compositions of the present invention may interact with warfarin, a drug that is used to thin the blood. Ginger can interact with the warfarin at doses greater than 5 g per day (Jellin J. M., et al. (2005). Pharmacist's Letter/Prescriber's Letter of Natural Medicines Comprehensive Database. 7th ed. Stockton, Calif.: Therapeutic Research Faculty). L-citrulline has no known side effects and no known reactions with any other pharmaceutical agents (see for example information available from Global Orphan Pharmaceutical LLC, and at web sites, such as citrullis.com/?page_id=2#SideEffects).

Studies conducted under the following protocol can demonstrate diagnosis, treatment and routine monitoring of erectile function and/or erectile dysfunction. In an embodiment, a treatment for preventing deterioration of one's erectile function, men treated with daily ginger (500 mg) and L-citrulline (1500 mg) in two divided doses would show no deterioration or less deterioration of their erectile function over time. The addition of paullina cupana (500 mg/day) and muira puama (500 mg /day) to daily ginger (500 mg) and L-citrulline (1500 mg) would not only prevent deterioration of erectile function as in the first study but would have an excellent chance of improving one's erectile function.

Exemplary formulations include at least ginger and at least one compound selected from the group consisting of L-arginine or L-citrulline. However, while the first two ingredients are ginger and L-arginine, L-arginine can be partially or completely replaced by L-citrulline, so collectively L-citrulline and L-arginine may be referred to as L-arginine since L-citrulline is converted to L-arginine in vivo. Formulation G-C (“Ginger-L-Citrulline), which comprises ginger and L-citrulline (preferably consists of about 100 mg to about 2 grams ginger and from about 500 mg to about 3 grams L-citrulline. Depending on cost, availability, purity, ease of compounding, shelf life, the ranges of compounds in the formulations and their rheological properties, preferred compositions of the present inventions include ginger and L-arginine (or L-citrulline). In another embodiment, in addition to ginger and L-citrulline or L-arginine, compositions of the present inventions can contain about 50 or 100 mg to about 2 grams Muira puama, about 5 mg to about 500 mg of cortex magnoliae officinalis (CMO), and about 5 mg to about 500 mg fructus aurantil immaturus.(FAI).

DIAGNOSTIC AND PROPHYLAXIS. Substantial barriers exist to conducting routine biopsies on corpus cavernosal (“CC”) tissue, e.g., pain, embarrassment, need to avoid erection until the biopsy wound heals, etc. Further, such biopsies must be repeated periodically. Patients must give informed consent before agreeing to the biopsies. Even a patient that has had a radical prostatectomy procedure that included a biopsy of the corporal tissue while under anesthesia may not be willing to have a follow up biopsy, even with assurances of provision of adequate pain relief and the promise that such biopsies can advance the field. Also, a significant problem confronting scientists and Institutional Review Board (IRB) panels is the need to conduct studies of the drug formulations on a double blind basis. So, half of the patients may receive a placebo in place of the drug formulation being tabulated; thus, there is a considerable difficulty in recruiting sufficient patients to provide biopsies, particularly when there is a considerable chance that a placebo will be administered instead of the drug formulation being tested. Further, IRBs may also desire that another study be performed in vitro and/or that animal studies could be used in place of some human studies. In some instances, such study designs may provide substantially the same and/or better data. Financial incentives to trial participants may not draw in a statistically representative group of subjects, and may not reflect a suitable sampling of the relevant population.

However, in a further embodiment of the present inventions, patient histories are collected and evaluated for the occurrence of ED. Patients that have prostate problems, urogenital disorders, and/or cancers in the genital area may be biopsied while under anesthesia for treatment (with prior written informed consent). Some patients may agree to give subsequent biopsy samples, while others will permit a sample to be taken at the time of death. By tracking sufficient family histories, and samples of tissue from patients exhibiting ED symptoms and patients with no ED symptoms, it is possible to identify genes involved in ED. Family histories of ED may also be useful in evaluating ED potential. By identifying patients that are susceptible to ED, even if symptoms have not yet manifested and/or not manifested sufficiently for an individual to require pharmaceutical assistance to achieve full erectile function, compositions of the present invention can be given to candidates while others will receive a placebo. Patients receiving compositions of the present invention that slow or halt ED symptom development, could then qualify for further studies to optimize ingredients, dosages, and period between dosages, etc. Patients that received the placebo and did not improve may be given the other formulation if statistically significant benefits are demonstrated. With sufficient patient data and DNA analysis, it will be possible to identify genetic predisposition to ED symptoms, and prophylaxis treatment can start at the expected age and/or when ED symptoms appear.

While details of certain embodiments of the present inventions are described, they are provided as illustrative examples so as to enable those of ordinary skill in the art to practice the inventions. The details provided are not meant to limit the scope of the present inventions, but to be exemplary. Where certain elements of the present inventions can be partially or fully implemented using known constituents, only those portions of such known constituents that are necessary for an understanding and making of the present invention are described, and detailed descriptions of other constituents or formulating processes are omitted as being to simplify explanation of the invention. Further, the present invention encompasses present and future known equivalents to the compositions and methods referred to herein. The inventions are capable of other embodiments and of being practiced and carried out in various ways, and as such, those skilled in the art will appreciate that the conception upon which this disclosure is based may readily be utilized as a basis for the designing of other methods and compositions for carrying out the several purposes of the present inventions. 

1. A composition comprising at least a first and at least a second compound, wherein said first compound is ginger and said second compound is selected from the group consisting of L-arginine and a compound that produces L-arginine in vivo, wherein administration of a pharmaceutically effective amount of said composition will treat erectile dysfunction by halting, slowing or reversing the deterioration of smooth muscle cells of the corporal cavernosum, wherein at least a portion of said ginger can be replaced with gingerol, wherein essential for said composition to treat erectile dysfunction are said ginger or said gingerol and said L-arginine or compound that produces L-arginine in vivo, wherein said composition comprises at least 250 mg ginger or an amount of gingerol sufficient to achieve the same effect in treating erectile dysfunction, and said composition comprises at least about 500 mg L-arginine, wherein said L-arginine can be in addition to or replaced by an amount of L-citrulline sufficient to produce substantially the same effect in vivo as said at least 500 mg of L-arginine, and wherein said composition is effective in treating erectile dysfunction without any other ingredients, and wherein the effective ingredients in said composition for treating erectile dysfunction consist essentially of said ginger, said gingerol, a combination of said ginger and said gingerol, said L-arginine, said L-citrulline or a combination of said L-arginine and said L-citrulline, and at least one compound selected from the group consisting of cortex magnoliae officinalis, fructus aurantil immaturus, Paullinia cupana, and Muira puama.
 2. The composition of claim 1, wherein a dose of said composition can be administered periodically to a subject for a sufficient period of time until erectile dysfunction is treated in the subject, and wherein the active ingredients in said composition for the treatment of erectile dysfunction consist essentially of said ginger, said gingerol, said Paullinia cupana, said Muira puama, and at least one of said L-arginine and said L-citrulline.
 3. The composition of claim 2, wherein said composition comprises at least about 50 mg Muira puama.
 4. The composition of claim 1, wherein said composition active ingredients for treating erectile dysfunction consist essentially of at least 250 mg ginger, at least 10 mg L-Citrulline, wherein when said composition contains no L-arginine a sufficient amount of L-Citrulline is present to have the equivalent in vivo effect as said L-arginine, at least about 50 mg Muira puama, and Paullinia cupana.
 5. A composition comprising a first and a second compound, wherein said first compound is ginger and said second compound is L-citrulline, wherein administration of a pharmaceutically effective amount of said composition will treat erectile dysfunction by halting, slowing or reversing the deterioration of smooth muscle cells of the corporal cavernosum, wherein said composition comprises at least 250 mg ginger or an amount of gingerol sufficient to achieve the same effect in treating erectile dysfunction, and wherein said composition can include as active ingredients to treat erectile dysfunction at least one of the group consisting of Muira Puama and Paullinia cupana, wherein ingredients in said composition essential to the treatment of erectile dysfunction consist essentially of said ginger and said L-citrulline, and wherein said essential ingredients can include compounds selected from the group consisting of one of the group consisting of Muira Puama and Paullina cupana.
 6. The composition of claim 5, wherein said composition comprises between at least 250 mg ginger and about 2 grams of ginger and further comprises 500 mg L-citrulline and 3 grams L-citrulline.
 7. (canceled)
 8. (Canceled)
 9. (canceled)
 10. A method of diagnosing and treating erectile dysfunction by evaluation of smooth muscle cell of the corpora cavernosa, and providing a pharmaceutically effective amount of a composition comprising ginger and L-citrulline or L-arginine.
 11. A method for treating erectile dysfunction, comprising the steps of administering to a patient an effective amount of a composition comprising ginger and L-arginine or a compound that produces L-arginine in vivo.
 12. The method of claim 9, further comprising repeating administering said composition to said patient over a period of time.
 13. The method of claim 13, wherein said composition is taken as a prophylaxis against erectile dysfunction. 